Obstetricians and reproductive biologists acknowledge that novel imaging tools are needed to assess the development of the placenta early in gestation in order to identify pregnancies at highest risk of adverse outcomes attributed to placental dysfunction. At our institution, we have utilized sophisticated 3D ultrasound technology and uterine artery Doppler velocimetry to study placental morphology and perfusion in relation to adverse pregnancy outcomes. We have enrolled approximately 1,000 women into our ultrasound studies, which are limited by low positive predictive values and the inability to manipulate 3D ultrasound image sets in real-time at the bedside. Consequently, we believe that a more precise and clinically useful assessment of placental structure and function will require advances in current technology and new partnerships between experts in technology and experts in clinical care of pregnant women. We propose a logical, but comprehensive approach utilizing ultrasound, MRI, and near-infrared spectroscopy (NIRS) to study placental morphology, perfusion, and oxygenation. We have assembled a diverse group of senior investigators at Penn who have substantial experience studying novel techniques and clinical applications for each of these imaging modalities, and our investigative team will be supported by clinical investigators with expertise in women's reproductive health (clinical perinatology, nutrition, and placental biology). The diverse investigative team will be crucial for analysis of data and decisions regarding research directions (go/no-go decisions) over the four- year funding period. Our ultimate objective is to develop a simple, clinically useful imaging modality that can be used at the bedside to identify women early in pregnancy who are at highest risk of developing pregnancy complications attributed to abnormal placental morphology, perfusion, and/or oxygenation. We will recruit women in our ultrasound unit into specific case-control and cohort studies that will focus on development and validation of 3D power Doppler ultrasound, functional MRI, and NIRS techniques. Cross-validation will be employed to identify the most clinically relevant imaging modalities. We then will perform a validation cohort study to determine the relationship among maternal nutrition (focusing on micronutrients in Western diets that induce an unfavorable redox environment), placental imaging (morphology, perfusion, and oxygenation), and neonatal anthropometrics. Specific aims are: 1) to develop and validate an automated ultrasound segmentation tool to standardize quantitative analysis of placenta morphology in vivo; 2) to develop and validate a quantitative MRI measure of placental perfusion; 3) to develop novel and non-invasive tools to quantify placental oxygenation using functional MRI and NIRS; and 4) to conduct a pilot study using the optimal measures obtained in aims 1-3 to study the impact of maternal nutritional status on placental development and function. We look forward to collaborating with the members of the HPP Technology Development Working Group who are funded by this exciting U01 cooperative agreement.